Episode-like pulse testosterone supplementation induces tumor senescence and growth arrest down-modulating androgen receptor through modulation of p-ERK1/2, pAR ser81 and CDK1 signaling: biological implications for men treated with testosterone replacement therapy

Despite the growing body of knowledge showing that testosterone (T) may not significantly affect tumor progression in hypogonadal patients treated for prostate cancer (Pca), the use of this hormone in this population still remains controversial. The effects of continuous or pulsed T stimulation were tested in vitro and in vivo on androgen-sensitive Pca cell lines in order to assess the differential biological properties of these two treatment modalities. Pulsed T treatment resulted in a greater inhibition than continuous T supplementation of tumor growth in vitro and in vivo. The effects of pulsed T treatment on tumor growth inhibition, G0/G1 cell cycle arrest, and tumor senescence was more pronounced than those obtained upon continuous T treatments. Mechanistic studies revealed that G0/G1 arrest and tumor senescence upon pulsed T treatment were associated with a marked decrease in cyclin D1, c-Myc and SKp2, CDK4 and p-Rb levels and upregulation of p27 and p-ERK1/2. Pulsed, but not continuous, T supplementation decreased the expression levels of AR, p-AR ser81 and CDK1 in both cellular models. The in vitro results were confirmed in an in vivo xenografts, providing evidence of a greater inhibitory activity of pulsed supraphysiological T supplementation than continuous treatment, both in terms of tumor volume and decreased AR, p-AR ser81 , PSA and CDK1 staining. The rapid cycling from hypogonadal to physiological or supra-physiological T intraprostatic concentrations results in cytostatic and senescence effects in preclinical models of androgen-sensitive Pca. Our preclinical evidence provides relevant new insights in the biology of Pca response to pulsed T supplementation

Fasting-Evoked En Route Hypoglycemia in Diabetes (FEEHD): An Overlooked Form of Hypoglycemia in Clinical Practice

Objective. Many patients with diabetes opt to fast for lab tests, especially for lipid profiles, thus missing breakfast. In parallel, recent studies and international guidelines have indicated that routine fasting for lipid panels may not be necessary. Missing breakfast while fasting for lab tests may invoke hypoglycemia, if patients are not properly instructed about adjusting diabetes medications on the night before or on the day of the lab test. Our group described this form of hypoglycemia and introduced the term FEEHD to refer to it (fasting-evoked en route hypoglycemia in diabetes). In a recently published small study, we reported a rate of occurrence of FEEHD of 27.1%. The objective of this study was to evaluate the rate of occurrence of FEEHD in another clinic. Methods. Patients with diabetes were asked to complete a simple, 2-page survey inquiring about hypoglycemic events while fasting for labs in the preceding 12 months. Results. A total of 525 patients completed the surveys out of 572 patients invited (91.8% response rate). A total of 363 patients with complete data were analyzed, with a mean age of 60.6 (SD 12.5) years. A total of 62 (17.1%) patients reported having experienced one or more FEEHD events in the prior 12 months. Of the 269 patients who were at higher risk of FEEHD (on insulin secretagogues or on insulin), 59 (21.9%) reported having experienced FEEHD. Only 33 of FEEHD patients (53%) recalled having contacted their provider regarding the events and only 22 (35%) indicated having received some sort of FEEHD prevention instructions. Conclusion. Our study shows a significant rate of occurrence of FEEHD in the real world (a clinical practice). FEEHD is especially dangerous, as patients often commute (drive) to and from the laboratory facility (potential risk of traffic accidents). Given study limitations, further studies are needed to assess prevalence of FEEHD in other settings and in the general populations

Functional and autoradiographic characterization of dopamine D2-like receptors in the guinea pig heart.

Dopamine receptors include the D1- (D1 and D5 subtypes) and D2-like (D2, D3, and D4 subtypes) families. D1-like receptors are positively and D2-like receptors negatively coupled to the adenylyl cyclase. Dopamine D2-like (D4 subtype) receptors have been identified in human and rat hearts. However the presence of D2 and D3 receptor subtypes is unclear. Furthermore, their role in cardiac functions is unknown. By autoradiographic studies of guinea pig hearts, we identified D3 and D4 receptors, using the selective radioligands [3H]-7-OH-DPAT and [3H]emonapride (YM-09151-2 plus raclopride). Western blot analysis confirmed D3 and D4 receptors in the right and left ventricle of the same species. Selective agonists of D3 and D4 receptors (+/-)-7-OH-DPAT and PD 168 077 (10(-9) to 10(-5) M, respectively) induced a significant negative chronotropic and inotropic effect in the isolated guinea pig heart preparation. Negative inotropic effect induced by PD 168 077 was associated with an inhibition in cyclase activity. No changes in cyclase activity were found with (+/-)-7-OH-DPAT. The aim of this study is to support the presence of D3 and D4 receptors in the heart. Although our results suggest that D3 and D4 receptors are functionally active in the heart, we need additional information with an antagonist and an agonist of improved potency and selectivity to understand the respective roles of D3 and D4 receptors in the cardiac functions